Advanced Drug Delivery Reviews 97 (2016) 4–27 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Extracellular matrix structure☆ Achilleas D. Theocharis a, Spyros S. Skandalis a, Chrysostomi Gialeli a,b, Nikos K. Karamanos a,⁎ a Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26500 Patras, Greece b Division of Medical Protein Chemistry, Department of Translational Medicine Malmö, Lund University, S-20502 Malmö, Sweden article info abstract Article history: Extracellular matrix (ECM) is a non-cellular three-dimensional macromolecular network composed of collagens, Received 1 September 2015 proteoglycans/glycosaminoglycans, elastin, fibronectin, laminins, and several other glycoproteins. Matrix com- Received in revised form 30 October 2015 ponents bind each other as well as cell adhesion receptors forming a complex network into which cells reside Accepted 2 November 2015 in all tissues and organs. Cell surface receptors transduce signals into cells from ECM, which regulate diverse cel- Available online 10 November 2015 lular functions, such as survival, growth, migration, and differentiation, and are vital for maintaining normal ho- Keywords: meostasis. ECM is a highly dynamic structural network that continuously undergoes remodeling mediated by Extracellular matrix several matrix-degrading enzymes during normal and pathological conditions. Deregulation of ECM composition Proteoglycans and structure is associated with the development and progression of several pathologic conditions. This article Glycosaminoglycans emphasizes in the complex ECM structure as to provide a better understanding of its dynamic structural and Collagen functional multipotency. Where relevant, the implication of the various families of ECM macromolecules in Matrix metalloproteases health and disease is also presented. Integrins © 2015 Elsevier B.V. All rights reserved. Pharmacological targeting Cancer Contents 1. Typesofextracellularmatrices:structureandproperties........................................... 5 2. ECMcomponents:structure,interactionsandfunctions........................................... 8 2.1. Proteoglycansandhyaluronan................................................... 8 2.1.1. Hyaluronan........................................................ 8 2.1.2. Proteoglycans....................................................... 8 2.2. Collagens.............................................................12 2.2.1. Fibrillarcollagens.....................................................13 2.2.2. Network-formingcollagens.................................................13 Abbreviations: ADAMs, a disintegrin and metalloproteases; ADAMTSs, ADAMs with thrombospondin motifs; BMPs, bone morphogenetic proteins; CSC, cancer stem cell; COMP, cartilage oligomeric matrix protein; CS, chondroitin sulfate; CSPG4, chondroitin sulfate proteoglycan 4; CNNs, cysteine-rich 61 connective tissue growth factor nephroblastoma overexpressed family proteins; DS, dermatan sulfate; DDRs, discoidin domain receptors; EMILIN-1, elastin microfibril interface located protein 1; ER, endoplasmic reticulum; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; EMT, epithelial-to-mesenchymal transition; ECMs, extracellular matrices; FACITs, fibril-associated collagens with interrupted triple helices; FGFs, fibroblast growth factors; FN, fibronectin; GAGs, glycosaminoglycans; GPI, glycosylphosphatidylinositol; Hh, Hedgehog; HS, heparan sulfate; HSPGs, hep- aran sulfate proteoglycans; Hep, heparin; HA, hyaluronan; HCC, hepatocellular cell carcinoma; HGF, hepatocyte growth factor; HASes, hyaluronan synthases; HYALs, hyaluronidases; HIF- 1α, hypoxia inducible factor-1α; IGF-IR, insulin-like growth factor-I receptor; IFP, interstitial fluid pressure; KS, keratan sulfate; LG, laminin globular; LCC, laminin coiled-coil; LN, laminin N-terminal; LE, laminin-type epidermal growth factor-like repeats; LDL, low density lipoprotein; LRP-1, LDL-receptor related protein-1; LOX, lysyl oxidase; MMPs, matrix metalloproteases; MACITs, membrane-associated collagens with interrupted triple helices; MT1-MMP, membrane type 1-MMP; MAGPs, microfibril-associated glycoproteins; MULTIPLEXIN, multiple triple-helix domains and interruptions; N-CAM, neural cell-adhesion molecule; NC, non-collagenous; OPN, osteopontin; PEDF, pigment epithelium-derived factor; PAIs, plasminogen activator inhibitors; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; PRELP, proline/arginine-rich end leucine-rich repeat protein; Pyk2, proline-rich tyrosine kinase 2; PKCα, protein kinase Cα;PGs,proteoglycans;RPTPβ, receptor-type protein tyrosine phosphatase β; RECK, reversion-inducing cysteine-rich protein with Kazal motifs; SEA, sea urchin sperm protein, enterokinase, and agrin; SPARC, secreted protein acidic and rich in cysteine; SLRPs, small leucine-rich proteoglycans; STIM1, stromal interaction molecule 1; TNs, tenascins; TN-C, tenascin-C; TN-X, tenascin-X; TN-W, tenascin-W; TSP-1, thrombospondin-1; TIMP-3, tissue inhibitor of metalloproteases-3; tPA, tissue- type plasminogen activator; TLRs, Toll-like receptors; TGF-β, transforming growth factor-β; TGFRI, TGF receptor I; TNF-α, tumor necrosis factor α; uPA, urokinase plasminogen activator; uPAR, urokinase plasminogen activator receptor; VEGFA, vascular endothelial growth factor A; VEGFR2, vascular endothelial growth factor receptor 2; Wnt, wingless-related integration site. ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Extracellular Matrix (ECM) and ECM-like materials: Therapeutic Tools and Targets in Cancer Treatment”. ⁎ Corresponding author. Tel.: +30 2610 997915. E-mail address: [email protected] (N.K. Karamanos). http://dx.doi.org/10.1016/j.addr.2015.11.001 0169-409X/© 2015 Elsevier B.V. All rights reserved. A.D. Theocharis et al. / Advanced Drug Delivery Reviews 97 (2016) 4–27 5 2.2.3. FACITs.......................................................... 13 2.2.4. MACITs......................................................... 13 2.2.5. Anchoring fibrils..................................................... 13 2.2.6. Beaded-filament-formingcollagens............................................. 13 2.2.7. MULTIPLEXIN....................................................... 13 2.3. Elastinandelastin-associatedproteins................................................ 14 2.4. Fibronectin............................................................ 14 2.5. Laminins............................................................. 15 2.6. Matricellularproteins:members,interactions,functions,androlesincancer.............................. 15 3. Extracellularmatrixproteases....................................................... 17 3.1. Matrixmetalloproteases...................................................... 17 3.2. Plasminogen/plasminsystem.................................................... 18 3.3. Cathepsinproteases........................................................ 18 4. Extracellularmatrixreceptors....................................................... 19 4.1. Integrins............................................................. 19 4.2. Discoidindomainreceptors.................................................... 19 4.3. CD44............................................................... 19 5. Extracellularmatrixtargeting:Noveltherapeuticapproaches......................................... 19 6. Conclusion............................................................... 20 Acknowledgments.............................................................. 21 References.................................................................. 21 1. Types of extracellular matrices: structure and properties the substrate for binding of epithelial cells, whereas collagen type IV network is localized at the stromal side. Epithelial cells are an- All tissues and organs contain a mixture of cells and non-cellular chored to basement membrane via specific structures named components, which form well-organized networks called extracellu- hemidesmosomes. They are formed when cell surface integrins inter- lar matrices (ECMs). The ECMs provide not only physical scaffolds act with laminins at the extracellular level and intracellularly with in- into which cells are embedded but also regulate many cellular pro- termediate filaments (Fig. 1) [7]. cesses including growth, migration, differentiation, survival, homeo- Cells embedded into ECMs interact with this macromolecular net- stasis, and morphogenesis [1–3]. The ECMs consist of a large variety work through their surface receptors, such as integrins, discoidin do- of matrix macromolecules whose precise composition and specific main receptors (DDRs), cell surface PGs, and the hyaluronan (HA) structures vary from tissue to tissue. The major constituents of receptor CD44. In this respect, cells integrate signals from ECMs that ECMs are fibrous-forming proteins, such as collagens, elastin, fibro- dictate their functions and behavior (Fig. 1).Allcelltypes(i.e.epi- nectin (FN), laminins, glycoproteins, proteoglycans (PGs), and gly- thelial, fibroblasts, immune cells, endothelial cells) synthesize and cosaminoglycans (GAGs), which are highly acidic and hydrated secrete matrix macromolecules under the control of multiple signals molecules. In most tissues, fibril-forming collagen type I and mainly thus participating in the formation